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1.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361069

RESUMO

Postmenopausal osteoporosis is closely associated with excessive osteoclast formation and function, resulting in the loss of bone mass. Osteoclast-targeting agents have been developed to manage this disease. We examined the effects of ciclopirox on osteoclast differentiation and bone resorption in vitro and in vivo. Ciclopirox significantly inhibited osteoclast formation from primary murine bone marrow macrophages (BMMs) in response to receptor activator of nuclear factor kappa B ligand (RANKL), and the expression of genes associated with osteoclastogenesis and function was decreased. The formation of actin rings and resorption pits was suppressed by ciclopirox. Analysis of RANKL-mediated early signaling events in BMMs revealed that ciclopirox attenuates IκBα phosphorylation without affecting mitogen-activated protein kinase activation. Furthermore, the administration of ciclopirox suppressed osteoclast formation and bone loss in ovariectomy-induced osteoporosis in mice and reduced serum levels of osteocalcin and C-terminal telopeptide fragment of type I collagen C-terminus. These results indicate that ciclopirox exhibits antiosteoclastogenic activity both in vitro and in vivo and represents a new candidate compound for protection against osteoporosis and other osteoclast-related bone diseases.


Assuntos
Antifúngicos/farmacologia , Reabsorção Óssea/tratamento farmacológico , Ciclopirox/farmacologia , Osteoclastos/citologia , Osteogênese , Ovariectomia/efeitos adversos , Substâncias Protetoras/farmacologia , Animais , Reabsorção Óssea/etiologia , Reabsorção Óssea/patologia , Diferenciação Celular , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Ligante RANK/genética , Ligante RANK/metabolismo
2.
Int J Biochem Cell Biol ; 137: 106033, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34216755

RESUMO

In clinical treatment, there is increasingly prevalent that traditional Chinese medicine treats common bone diseases including osteoporosis. Hydroxysafflor yellow A (HSYA), one of the essential compounds of Safflower, has been used as the therapy for thrombus, myocardial ischemia, and inflammation, but its effect on osteogenesis through epigenetic control and ovariectomy-induced bone loss in vivo has not been explored. Therefore, the study aimed to explore the function and mechanism of HSYA on bone formation and development. We found HSYA could enhance the cell viability and promote osteogenesis of hBMSCs in vitro. Mechanistically, HSYA could increase the expression of ß-catenin leading to its accumulation in the nucleus and activation of downstream targets to promote osteogenesis. Besides, RNA-seq and quantitative RT-PCR and western blot showed KDM7A was significantly increased by HSYA. The occupancy of H3K27me2 on ß-catenin promoter was significantly decreased by HSYA, which could be reversed by silencing endogenous KDM7A. More importantly, HSYA promoted bone development in chick embryos and prevented ovariectomy (OVX)-induced bone loss in SD rats. Taken together, our study has shown convincing evidence that HSYA could promote osteogenesis and bone development via epigenetically regulating ß-catenin and prevent ovariectomy-induced bone loss.


Assuntos
Desenvolvimento Ósseo/efeitos dos fármacos , Chalcona/análogos & derivados , Osteogênese , Osteoporose/tratamento farmacológico , Ovariectomia/efeitos adversos , Quinonas/farmacologia , beta Catenina/metabolismo , Animais , Proliferação de Células , Chalcona/farmacologia , Feminino , Osteoporose/etiologia , Osteoporose/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , beta Catenina/genética
3.
Biochem Cell Biol ; 99(4): 488-498, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34297624

RESUMO

Although tumor necrosis factor α (TNF-α)-mediated inflammation significantly impacts osteoporosis, the mechanisms underlying the osteogenic differentiation defects of bone marrow-derived mesenchymal stem cells (BM-MSCs) caused by TNF-α remain poorly understood. We found that TNF-α stimulation of murine BM-MSCs significantly upregulated the expression levels of several microRNAs (miRNAs), including let-7f-5p, but this increase was significantly reversed by treatment with the kinase inhibitor BAY 11-7082. To study gain- or loss of function, we transfected cells with an miRNA inhibitor or miRNA mimic. We then demonstrated that let-7f-5p impaired osteogenic differentiation of BM-MSCs in the absence and presence of TNF-α, as evidenced by alkaline phosphatase and alizarin red staining as well as quantitative assays of the mRNA levels of bone formation marker genes in differentiated BM-MSCs. Moreover, let-7f-5p targets the 3' untranslated region of Nucleoside diphosphate kinase 4 (Nme4) mRNA and negatively regulates Nme4 expression in mouse BM-MSCs. Ectopic expression of Nme4 completely reversed the inhibitory effects of the let-7f-5p mimic on osteogenic differentiation of mouse BM-MSCs. Furthermore, inhibition of let-7f-5p or overexpression of Nme4 in BM-MSCs restored in-vivo bone formation in an ovariectomized animal model. Collectively, our work indicates that let-7f-5p is involved in TNF-α-mediated reduction of BM-MSC osteogenesis via targeting Nme4.


Assuntos
Reabsorção Óssea/patologia , Diferenciação Celular , Células-Tronco Mesenquimais/patologia , MicroRNAs/genética , Nucleosídeo Difosfato Quinase D/metabolismo , Osteogênese , Fator de Necrose Tumoral alfa/toxicidade , Animais , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Feminino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nucleosídeo Difosfato Quinase D/genética , Ovariectomia/efeitos adversos
4.
Maturitas ; 150: 22-29, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34274072

RESUMO

OBJECTIVES: While it has been reported that women with uterine fibroids or endometriosis are commonly overweight and hypertensive, the association between non-malignant gynecological diseases and the risk of hypertension has been little studied prospectively. The aim of this study was to investigate in a large French cohort of women whether a history of hysterectomy, uterine fibroids, or endometriosis was prospectively related to an increased risk of incident hypertension. STUDY DESIGN: We analyzed 50,286 women from the E3N cohort who were free of hypertension at baseline, with a median follow-up of 16.4 years. MAIN OUTCOME MEASURES: Gynecological diseases were based on self-report. Cox proportional hazards models with age as the timescale were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Covariates included smoking status, body mass index (BMI), physical activity, and hormonal factors. RESULTS: A total of 12,073 women (24%) developed hypertension during follow-up. Women with a history of hysterectomy had an increased risk of incident hypertension, which persisted after adjustment for potential confounding factors (adjusted HR=1.18, 95% CI 1.12-1.24). Risk was similar in women with hysterectomy with or without oophorectomy. Risk of hypertension was higher in women with a history of endometriosis (HRendometriosis 1.19, 95%CI 1.11-1.22) or uterine fibroids (HRfibroids 1.18, 95%CI 1.13-1.22), irrespective of hysterectomy. Associations were similar after further adjustment for BMI. CONCLUSIONS: Hysterectomy and non-malignant gynecological diseases were associated with an increased risk of hypertension in this large prospective study. Women with these conditions may benefit from blood pressure monitoring. ClinicalTrials.gov identifier: NCT03285230.


Assuntos
Índice de Massa Corporal , Doenças dos Genitais Femininos/cirurgia , Hipertensão/etiologia , Histerectomia/efeitos adversos , Ovariectomia/efeitos adversos , Adulto , Idoso , Feminino , França/epidemiologia , Humanos , Hipertensão/epidemiologia , Hipertensão/patologia , Incidência , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
5.
Biomed Pharmacother ; 139: 111697, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243614

RESUMO

Excessive osteoclast activity, along with relatively weak osteoblast function, is strongly associated with bone disease. Therefore, studies to identify novel anti-osteoporosis candidates with dual actions of inhibiting osteoclastogenesis and increasing osteoblastogenesis may provide an ideal approach for treating osteoporosis. Pitavastatin, an inhibitor of 3-hydroxy-3 methyl-glutaryl coenzyme A reductase, has demonstrated various pharmacological activities, including anti-inflammation, bone anabolic effects, vasodilation, and inhibition of revascularization; however, the precise effects and mechanisms of pitavastatin on the regulation of osteoblast and osteoclast activity need to be comprehensively elucidated. Herein, we demonstrated that pitavastatin is a potential candidate for treating osteoporosis by enhancing osteoblast differentiation and bone growth and inhibiting osteoclast differentiation and bone resorption. Pitavastatin exerted dose-dependent inhibitory effects on receptor activator of nuclear factor kappa-B ligand-induced osteoclast formation, bone resorption, and osteoclast-specific marker gene expression. These inhibitory effects were achieved by inhibiting the Akt, NF-κB, and mitogen-activated protein kinase (p38, ERK, and JNK) signaling pathways, resulting in the downregulation of major transcription factors c-Fos and NFATc1. Furthermore, pitavastatin potentially stimulated osteoblast differentiation by activating alkaline phosphatase (ALP), enhancing mineralization by Alizarin Red S, and increasing the expression of osteoblastogenic marker genes such as runt-related transcription factor 2, ALP, osteocalcin, and collagen type 1 alpha. Furthermore, we evaluated the therapeutic potential of pitavastatin in ovariectomy-induced systematic bone loss based on micro-computed tomography and histological analysis of femurs. Our findings demonstrated a new function and mechanism for pitavastatin in bone remodeling, indicating its potential as a therapeutic candidate in treating osteoporosis by inhibiting osteoclastic resorption and promoting osteoblastic formation.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Ovariectomia/efeitos adversos , Quinolinas/farmacologia , Animais , Biomarcadores/metabolismo , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Feminino , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Molecules ; 26(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198932

RESUMO

The effects of the phytoestrogen-enriched plant Pueraria mirifica (PM) extract on ovari-ectomy (OVX)-induced cognitive impairment and hippocampal oxidative stress in mice were investigated. Daily treatment with PM and 17ß-estradiol (E2) significantly elevated cognitive behavior as evaluated by using the Y maze test, the novel object recognition test (NORT), and the Morris water maze test (MWM), attenuated atrophic changes in the uterus and decreased serum 17ß-estradiol levels. The treatments significantly ameliorated ovariectomy-induced oxidative stress in the hippocampus and serum by a decrease in malondialdehyde (MDA), an enhancement of superoxide dismutase, and catalase activity, including significantly down-regulated expression of IL-1ß, IL-6 and TNF-α proinflammatory cytokines, while up-regulating expression of PI3K. The present results suggest that PM extract suppresses oxidative brain damage and dysfunctions in the hippocampal antioxidant system, including the neuroinflammatory system in OVX animals, thereby preventing OVX-induced cognitive impairment. The present results indicate that PM exerts beneficial effects on cognitive deficits for which menopause/ovariectomy have been implicated as risk factors.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Hipocampo/metabolismo , Ovariectomia/efeitos adversos , Fitoestrógenos/administração & dosagem , Pueraria/química , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Estradiol/administração & dosagem , Estradiol/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Malondialdeído/sangue , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Fitoestrógenos/química , Fitoestrógenos/farmacologia
7.
Biomed Res Int ; 2021: 5510124, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34055972

RESUMO

Objectives: To establish a novel animal model of intervertebral disc degeneration (IVDD) in rats and to investigate the effect of 17ß-estradiol (E2) intervention in this model. Methods: This study was divided into two parts: animal model (four groups: Sham, ovariectomy (OVX), Puncture, and OVX+Puncture; three-time points: 4, 8, and 12 weeks; three female rats/group/time point) and drug intervention (Sham, OVX+Puncture+corn oil, and OVX+Puncture+E2; three female rats/group). The rats were analyzed by micromagnetic resonance imaging (MRI), hematoxylin and eosin (HE) staining, and safranin-O staining. Results: MRI and histological scores significantly differed among the four groups at the three-time points (all P < 0.05). IVDD progressed with time in the OVX, Puncture, and OVX+Puncture groups (all P < 0.05). The changes were the most obvious in the OVX+Puncture group. In the E2 intervention part, the Veh group had the worst MRI signals and histological scores (P < 0.05). The MRI scores in the E2 group were less obvious compared to the Sham group (P > 0.05). Also, the histological scores were significantly different between the Sham and E2 groups (P < 0.05). Conclusions: The combination of ovariectomy and needle puncture can synergically induce IVDD in rat coccygeal discs. Estrogen treatment can effectively ameliorate IVDD progression in the newly established IVDD models.


Assuntos
Degeneração do Disco Intervertebral , Agulhas/efeitos adversos , Ovariectomia/efeitos adversos , Punções/efeitos adversos , Animais , Modelos Animais de Doenças , Estradiol/farmacologia , Estrogênios , Feminino , Disco Intervertebral/diagnóstico por imagem , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/patologia , Imageamento por Ressonância Magnética , Ratos , Ratos Sprague-Dawley
8.
Eur J Pharmacol ; 905: 174207, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34048742

RESUMO

The majority of women experience vasomotor symptoms (VMS), such as hot flashes and night sweats, during the menopausal transition. Recent evidence strongly suggests a connection between neurokinin 3 (NK3) receptor signaling and VMS associated with menopause. The NK3 receptor antagonist fezolinetant is currently in phase 3 development for treatment of moderate to severe VMS associated with menopause. We investigated the pharmacological effects of repeated administration of fezolinetant on levels of sex hormones and gonadotropins, neuronal activity in the hypothalamus, and skin temperature as an index of hot flash-like symptoms in ovariectomized rats as a model of menopause. Ovariectomized rats exhibited several typical menopausal symptoms: hyperphagia, increased body weight, significantly decreased plasma estradiol levels, increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and significantly increased skin temperature. Increased c-Fos expression (an indirect marker of neuronal activity) in median preoptic nucleus (MnPO) hypothalamic neurons was also observed in ovariectomized rats. Repeated oral administration of fezolinetant (1-10 mg/kg, twice daily) for 1 week dose-dependently reduced plasma LH levels without affecting estradiol or FSH levels, inhibited the activation of MnPO neurons, and attenuated hot flash-like symptoms. In addition, fezolinetant dose-dependently reduced hyperphagia and weight gain in ovariectomized rats. These preclinical findings suggest that fezolinetant attenuates hot flash-like symptoms via inhibition of neuronal activity in the MnPO of ovariectomized rats and provides further support for the ongoing clinical development of fezolinetant for the treatment of VMS associated with menopause.


Assuntos
Compostos Heterocíclicos com 2 Anéis/farmacologia , Fogachos/tratamento farmacológico , Receptores da Neurocinina-3/antagonistas & inibidores , Tiadiazóis/farmacologia , Administração Oral , Animais , Temperatura Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Compostos Heterocíclicos com 2 Anéis/administração & dosagem , Fogachos/etiologia , Injeções Subcutâneas , Hormônio Luteinizante/sangue , Menopausa/efeitos dos fármacos , Ovariectomia/efeitos adversos , Área Pré-Óptica/metabolismo , Progesterona/sangue , Ratos Wistar , Temperatura Cutânea/efeitos dos fármacos , Testosterona/sangue , Tiadiazóis/administração & dosagem
9.
BMC Vet Res ; 17(1): 181, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33933076

RESUMO

BACKGROUND: As one of the most common surgeries performed in veterinary medicine, ovariohysterectomy (OHE) can induce oxidative stress in dogs. The antioxidant properties of melatonin have been confirmed in various studies. This study aimed to investigate the effects of melatonin administration on oxidative stress in dogs before and after OHE. In this study, 25 mature female intact dogs were selected and randomly divided into five equal groups: Melatonin (melatonin, no surgery), OHE (no melatonin, surgery), OHE + melatonin (melatonin, surgery), anesthesia+melatonin (melatonin, sham surgery), and control (no melatonin, no surgery) groups. Melatonin (0.3 mg/Kg/day, p.o.) was administrated to the dogs in the melatonin, OHE + melatonin, and anesthesia+melatonin groups on days - 1, 0, 1, 2, and 3 (day 0 = OHE). Blood sampling was performed on days - 1, 1, 3, and 5 of the study. Blood samples were immediately transferred to the laboratory and sera were separated and stored at - 20 °C. Superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT) and malondialdehyde (MDA) concentrations were measured with commercial kits. RESULTS: The levels of SOD, GPX and CAT were significantly higher in the melatonin and anesthesia+melatonin groups compared to those of the control group at days 3 and 5. The level of antioxidant enzymes significantly decreased in the OHE group compared to that of other groups at days 3 and 5. The administration of melatonin increased the level of antioxidant enzymes in ovariohysterectomized dogs. Ovariohysterectomy significantly increased the concentration of MDA in comparison to that of other groups at day 3. Melatonin administration significantly decreased the level of MDA in melatonin, anesthetized, and ovariohysterectomized dogs at day 3. CONCLUSIONS: Administration of melatonin on day - 1, 0, 1, 2 and 3 modulate the oxidative stress induced by OHE in dogs by increasing antioxidant enzymes concentration and decreasing MDA levels.


Assuntos
Histerectomia/veterinária , Melatonina/farmacologia , Ovariectomia/veterinária , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Catalase/sangue , Cães , Feminino , Glutationa Peroxidase/sangue , Histerectomia/efeitos adversos , Malondialdeído/sangue , Ovariectomia/efeitos adversos , Superóxido Dismutase/sangue
10.
J Ethnopharmacol ; 275: 114096, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33823166

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The increasing use of "kidney"-nourishing Traditional Chinese Medicine (TCM) like Er-xian decoction (EXD) for management of menopausal symptoms and osteoporosis has aroused concerns about their safety, and whether they interact with prescription drugs as both of them act via estrogen receptors (ERs) and regulate serum estradiol. AIM OF THE STUDY: The present study aimed to evaluate whether EXD selectively exerted estrogenic activities and interacted with Selective Estrogen Receptor Modulators (SERMs). MATERIALS AND METHODS: In vivo, mature ovariectomized (OVX) rats were administrated with EXD or combined treatment of EXD and SERMs for 12 weeks. The tissue-selective effect of EXD and its interaction of SERMs were studied in four estrogen sensitive tissues, bone, brain, breast and uterus. In vitro, the interaction of extracts of EXD-treated serum and SERMs in four ER-positive cell lines. RESULTS: In OVX rats, EXD selectively alleviated estrogen deficiency-induced changes in the bone and brain without inducing any estrogenic effects in the breast or uterus. Two-way ANOVA indicated the presence of interactions between EXD and SERMs in OVX rats but EXD did not significantly alter the tissue responses to SERMs in the bone, breast or brain. Indeed, the combined use of EXD and SERMs appeared to suppress the estrogenic effect of raloxifene and tamoxifen in the uterus. Extract of EXD-treated serum directly stimulated cell proliferation or differentiation in human osteosarcoma MG-63, neuroblastoma SHSY5Y, breast cancer MCF-7, and endometrial Ishikawa cells. Two-way ANOVA revealed that EXD-treated serum interacted with SERMs at various concentrations and altered the effects of tamoxifen in MG-63 and MCF-7 cells. CONCLUSIONS: EXD exerted estrogenic effects in a tissue-selective manner and interacted with SERMs. Combined treatment of EXD and SERMs did not hamper the beneficial effects of SERMs on the bone or brain but appeared to moderate the estrogenic effect of SERMs in the uterus.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Estrogênios/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Linhagem Celular Tumoral , Sistema Nervoso Central/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Estradiol/farmacologia , Estradiol/uso terapêutico , Estrogênios/química , Estrogênios/uso terapêutico , Feminino , Interações Ervas-Drogas/fisiologia , Hormônios/sangue , Humanos , Glândulas Mamárias Humanas/efeitos dos fármacos , Medicina Tradicional Chinesa , Modelos Biológicos , Ovariectomia/efeitos adversos , Cloridrato de Raloxifeno/farmacologia , Cloridrato de Raloxifeno/uso terapêutico , Ratos Sprague-Dawley , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Útero/efeitos dos fármacos , Útero/metabolismo , Útero/patologia , Água
11.
Biochem Pharmacol ; 188: 114579, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33895161

RESUMO

Osteolytic diseases, including breast cancer-induced osteolysis and postmenopausal osteoporosis, are attributed to excessive bone resorption by osteoclasts. Spleen tyrosine kinase (SYK) is involved in osteoclastogenesis and bone resorption, whose role in breast cancer though remains controversial. Effects of PRT062607 (PRT), a highly specific inhibitor of SYK, on the osteoclast and breast cancer functionalities are yet to be clarified. This study demonstrated the in vitro inhibitory actions of PRT on the osteoclast-specific gene expression, bone resorption, and osteoclastogenesis caused by receptor activator of nuclear factor kappa B ligand (RANKL), as well as its in vitro suppressive effects on the growth, migration and invasion of breast carcinoma cell line MDA-MB-231, which were achieved through PLCγ2 and PI3K-AKT-mTOR pathways. Further, we proved that PRT could prevent post-ovariectomy (OVX) loss of bone and breast cancer-induced bone destruction in vivo, which agreed with the in vitro outcomes. In conclusion, our findings suggest the potential value of PRT in managing osteolytic diseases mediated by osteoclasts.


Assuntos
Neoplasias da Mama/enzimologia , Cicloexilaminas/uso terapêutico , Osteólise/enzimologia , Ovariectomia/efeitos adversos , Pirimidinas/uso terapêutico , Quinase Syk/antagonistas & inibidores , Quinase Syk/metabolismo , Animais , Reabsorção Óssea/enzimologia , Reabsorção Óssea/patologia , Reabsorção Óssea/prevenção & controle , Neoplasias da Mama/patologia , Neoplasias da Mama/prevenção & controle , Linhagem Celular Tumoral , Cicloexilaminas/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Osteólise/patologia , Osteólise/prevenção & controle , Pirimidinas/farmacologia
12.
J Pharmacol Sci ; 146(1): 49-57, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33858655

RESUMO

We performed clinical retrospective study in female cancer patients and fundamental experiments in mice, in order to clarify risk factors for paclitaxel-induced peripheral neuropathy (PIPN). In the clinical study, 131 of 189 female outpatients with cancer undergoing paclitaxel-based chemotherapy met inclusion criteria. Breast cancer survivors (n = 40) showed significantly higher overall PIPN (grades 1-4) incidence than non-breast cancer survivors (n = 91). Multivariate sub-analyses of breast cancer survivors showed that 57 years of age or older and endocrine therapy before paclitaxel treatment were significantly associated with severe PIPN (grades 2-4). The age limit was also significantly correlated with overall development of severe PIPN. In the preclinical study, female mice subjected to ovariectomy received repeated administration of paclitaxel, and mechanical nociceptive threshold was assessed by von Frey test. Ovariectomy aggravated PIPN in the mice, an effect prevented by repeated treatment with 17ß-estradiol. Repeated administration of thrombomodulin alfa (TMα), known to prevent chemotherapy-induced peripheral neuropathy in rats and mice, also prevented the development of PIPN in the ovariectomized mice. Collectively, breast cancer survivors, particularly with postmenopausal estrogen decline and/or undergoing endocrine therapy, are considered a PIPN-prone subpopulation, and may require non-hormonal pharmacological intervention for PIPN in which TMα may serve as a major candidate.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Estrogênios/deficiência , Estrogênios/fisiologia , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Animais , Neoplasias da Mama , Sobreviventes de Câncer , Feminino , Humanos , Camundongos , Camundongos Endogâmicos , Pessoa de Meia-Idade , Ovariectomia/efeitos adversos , Doenças do Sistema Nervoso Periférico/prevenção & controle , Pós-Menopausa , Ratos , Estudos Retrospectivos , Fatores de Risco , Trombomodulina/administração & dosagem
13.
Am J Physiol Endocrinol Metab ; 320(6): E1020-E1031, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33870713

RESUMO

We recently reported that compared with males, female mice have increased hepatic mitochondrial respiratory capacity and are protected against high-fat diet-induced steatosis. Here, we sought to determine the role of estrogen in hepatic mitochondrial function, steatosis, and bile acid metabolism in female mice and investigate potential benefits of exercise in the absence or presence of estrogen via ovariectomy (OVX). Female C57BL mice (n = 6 per group) were randomly assigned to sham surgery (sham), ovariectomy (OVX), or OVX plus estradiol replacement therapy (OVX + Est). Half of the mice in each treatment group were sedentary (SED) or had access to voluntary wheel running (VWR). All mice were fed a high-fat diet (HFD) and were housed at thermoneutral temperatures. We assessed isolated hepatic mitochondrial respiratory capacity using the Oroboros O2k with both pyruvate and palmitoylcarnitine as substrates. As expected, OVX mice presented with greater hepatic steatosis, weight gain, and fat mass gain compared with sham and OVX + Est animals. Hepatic mitochondrial coupling (basal/state 3 respiration) with pyruvate was impaired following OVX, but both VWR and estradiol treatment rescued coupling to levels greater than or equal to sham animals. Estradiol and exercise also had different effects on liver electron transport chain protein expression depending on OVX status. Markers of bile acid metabolism and excretion were also impaired by ovariectomy but rescued with estradiol add-back. Together our data suggest that estrogen depletion impairs hepatic mitochondrial function and liver health, and that estradiol replacement and modest exercise can aid in rescuing this phenotype.NEW & NOTEWORTHY OVX induces hepatic steatosis in sedentary mice which can be prevented by modest physical activity (VWR) and/or estradiol treatment. Estrogen impacts hepatic mitochondrial coupling in a substrate-specific manner. OVX mice have impaired fecal bile acid excretion, which was rescued with estradiol treatment.


Assuntos
Estradiol/uso terapêutico , Fígado Gorduroso/prevenção & controle , Fígado/fisiopatologia , Mitocôndrias Hepáticas/fisiologia , Ovariectomia , Condicionamento Físico Animal/fisiologia , Animais , Terapia Combinada , Estradiol/farmacologia , Terapia por Exercício , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Fígado Gorduroso/fisiopatologia , Feminino , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/efeitos dos fármacos , Ovariectomia/efeitos adversos
14.
Genes (Basel) ; 12(3)2021 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800915

RESUMO

Osteoporosis, characterized by reduced bone mass and increased bone fragility, is a disease prevalent in women. Likewise, breast cancer is a multifactorial disease and considered the major cause of mortality in premenopausal and postmenopausal women worldwide. Our data demonstrated the association of the MYLK gene and PTGS1 gene variants with osteoporosis and benign breast tumor risk and the impact of ovariectomy on osteoporosis in Korean women. We performed a genome-wide association study (GWAS) of women with osteoporosis and benign breast tumors. There were 60 single nucleotide polymorphisms (SNPs) and 12 SNPs in the MYLK and PTGS1 genes, associated with benign breast tumors and osteoporosis. Our study showed that women with homozygous MYLK rs12163585 major alleles had an increased risk of osteoporosis following ovariectomy compared to those with minor alleles. Women carrying the minor PTGS1 rs1213265 allele and not treated via ovariectomy carried a higher risk of osteoporosis than those who underwent ovariectomy with a homozygous genotype at the major alleles. Our results suggest that both the MYLK and PTGS1 genes are genetic factors associated with the phenotypes, and these associations appear to be modulated by ovariectomy.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação ao Cálcio/genética , Ciclo-Oxigenase 1/genética , Quinase de Cadeia Leve de Miosina/genética , Osteoporose/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Ovariectomia/efeitos adversos , Fenótipo , República da Coreia
15.
World J Surg Oncol ; 19(1): 132, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33882931

RESUMO

BACKGROUND: To compare the postoperative recurrence and fertility in patients with borderline ovarian tumors (BOTs) who underwent different surgical procedures: salpingo-oophorectomy versus cystectomy. METHODS: Potentially relevant literature from inception to Nov. 06, 2020, were retrieved in databases including Cochrane Library, EMBASE (Ovid), and MEDLINE (Pubmed). We applied the keywords "fertility-sparing surgery," or "conservative surgery," or "cystectomy," or "salpingo-oophorectomy," or "oophorectomy," or "adnexectomy," or "borderline ovarian tumor" for literate searching. Systemic reviews and meta-analyses were performed on the postoperative recurrence rates and pregnancy rates between patients receiving the two different surgical methods. Begger's methods, Egger's methods, and funnel plot were used to evaluate the publication bias. RESULT: Among the sixteen eligible studies, the risk of recurrence was evaluated in all studies, and eight studies assessed the postoperative pregnancy rates in the BOT patients. A total of 1839 cases with borderline ovarian tumors were included, in which 697 patients (37.9%) received unilateral salpingo-oophorectomy and 1142 patients (62.1%) underwent unilateral/bilateral cystectomy. Meta-analyses showed that BOT patients with unilateral/bilateral cystectomy had significantly higher recurrence risk (OR=2.02, 95% CI: 1.59-2.57) compared with those receiving unilateral salpingo-oophorectomy. Pooled analysis of four studies further confirmed the higher risk of recurrence in patients with cystectomy (HR=2.00, 95% CI: 1.11-3.58). In addition, no significant difference in postoperative pregnancy rate was found between patients with the two different surgical procedures (OR=0.92, 95% CI: 0.60-1.42). CONCLUSION: Compared with the unilateral/bilateral cystectomy, the unilateral salpingo-oophorectomy significantly reduces the risk of postoperative recurrence in patients with BOT, and it does not reduce the pregnancy of patients after surgery. TRIAL REGISTRATION: PROSPERO CRD42021238177.


Assuntos
Preservação da Fertilidade , Infertilidade Feminina , Neoplasias Ovarianas , Ovariectomia , Salpingo-Ooforectomia , Feminino , Humanos , Infertilidade Feminina/etiologia , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Cistos Ovarianos/patologia , Cistos Ovarianos/cirurgia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Ovariectomia/efeitos adversos , Gravidez , Prognóstico , Estudos Retrospectivos , Salpingo-Ooforectomia/efeitos adversos
16.
Int J Mol Sci ; 22(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33926097

RESUMO

Ovarian hormone deficiency leads to increased body weight, visceral adiposity, fatty liver and disorders associated with menopausal metabolic syndrome. To better understand the underlying mechanisms of these disorders in their early phases of development, we investigated the effect of ovariectomy on lipid and glucose metabolism. Compared to sham-operated controls, ovariectomized Wistar female rats markedly increased whole body and visceral adipose tissue weight (p ˂ 0.05) and exhibited insulin resistance in peripheral tissues. Severe hepatic triglyceride accumulation (p ˂ 0.001) after ovariectomy preceded changes in both serum lipids and glucose intolerance, reflecting alterations in some CYP proteins. Increased CYP2E1 (p ˂ 0.05) and decreased CYP4A (p ˂ 0.001) after ovariectomy reduced fatty acid oxidation and induced hepatic steatosis. Decreased triglyceride metabolism and secretion from the liver contributed to hepatic triglyceride accumulation in response to ovariectomy. In addition, interscapular brown adipose tissue of ovariectomized rats exhibited decreased fatty acid oxidation (p ˂ 0.01), lipogenesis (p ˂ 0.05) and lipolysis (p ˂ 0.05) despite an increase in tissue weight. The results provide evidence that impaired hepatic triglycerides and dysregulation of some CYP450 proteins may have been involved in the development of hepatic steatosis. The low metabolic activity of brown adipose tissue may have contributed to visceral adiposity as well as triglyceride accumulation during the postmenopausal period.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Transtornos do Metabolismo dos Lipídeos/etiologia , Metabolismo dos Lipídeos/fisiologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Sistema Enzimático do Citocromo P-450/fisiologia , Dieta Hiperlipídica , Dislipidemias/metabolismo , Fígado Gorduroso/metabolismo , Feminino , Glucose/metabolismo , Insulina/metabolismo , Resistência à Insulina , Gordura Intra-Abdominal/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Transtornos do Metabolismo dos Lipídeos/fisiopatologia , Lipídeos/sangue , Lipogênese/efeitos dos fármacos , Lipólise , Fígado/metabolismo , Menopausa/metabolismo , Menopausa/fisiologia , Obesidade/metabolismo , Ovariectomia/efeitos adversos , Pós-Menopausa/metabolismo , Pós-Menopausa/fisiologia , Ratos , Ratos Wistar , Triglicerídeos/metabolismo , Ganho de Peso
17.
BMC Pregnancy Childbirth ; 21(1): 321, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33892651

RESUMO

BACKGROUND: A uterine manipulator cannot be used to elevate the ovary in benign ovarian surgery during pregnancy. This report describes our method of elevation of the ovary using a metreurynter with the success rate of the procedure and a comparison of surgical results and pregnancy outcomes between the successful and unsuccessful cases. METHODS: Between August 2003 and February 2020, 11 pregnant patients with a tumor found sunk in the Cul-de-sac underwent laparoscopic cystectomy for a benign ovarian cyst with a metreurynter. The surgical results, success and failure of the elevation by a metreurynter, pregnancy outcomes, and fetal status at delivery were evaluated. RESULTS: Elevation of ovarian tumors with a metreurynter was successful in nine cases. However, it was unsuccessful in the remaining two cases wherein the ovary was lifted with forceps while the uterus was in a compressed state. The operative time was also longer in these cases. The pregnancy prognosis, however, was good for both, successful and unsuccessful cases. CONCLUSIONS: The metreurynter is an inexpensive and practical obstetric device, and its optimal use allows the performance of a procedure with minimal burden on a pregnant uterus. Therefore, we recommend the appropriate use of this method to enable effective laparoscopic cystectomy of ovarian tumors during pregnancy.


Assuntos
Escavação Retouterina/cirurgia , Complicações Intraoperatórias , Laparoscopia , Cistos Ovarianos , Ovariectomia , Complicações na Gravidez , Instrumentos Cirúrgicos , Adulto , Feminino , Humanos , Complicações Intraoperatórias/etiologia , Complicações Intraoperatórias/prevenção & controle , Laparoscopia/efeitos adversos , Laparoscopia/instrumentação , Laparoscopia/métodos , Remoção/efeitos adversos , Duração da Cirurgia , Cistos Ovarianos/patologia , Cistos Ovarianos/cirurgia , Ovariectomia/efeitos adversos , Ovariectomia/métodos , Pneumoperitônio Artificial/métodos , Gravidez , Complicações na Gravidez/patologia , Complicações na Gravidez/cirurgia , Resultado da Gravidez , Instrumentos Cirúrgicos/efeitos adversos , Instrumentos Cirúrgicos/classificação , Útero/lesões
18.
J Cell Mol Med ; 25(9): 4287-4297, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33768674

RESUMO

Osteoclasts (OCs) play important roles in bone remodelling and contribute to bone loss by increasing bone resorption activity. Excessively activated OCs cause diverse bone disorders including osteoporosis. Isovaleric acid (IVA), also known as 3-methylbutanoic acid is a 5-carbon branched-chain fatty acid (BCFA), which can be generated by bacterial fermentation of a leucine-rich diet. Here, we find that IVA suppresses differentiation of bone marrow-derived macrophages into OCs by RANKL. IVA inhibited the expression of OC-related genes. IVA-induced inhibitory effects on OC generation were attenuated by pertussis toxin but not by H89, suggesting a Gi -coupled receptor-dependent but protein kinase A-independent response. Moreover, IVA stimulates AMPK phosphorylation, and treatment with an AMPK inhibitor blocks IVA-induced inhibition of OC generation. In an ovariectomized mouse model, addition of IVA to the drinking water resulted in significant decrease of body weight gain and inhibited the expression of not only OC-related genes but also fusogenic genes in the bone tissue. IVA exposure also blocked bone destruction and OC generation in the bone tissue of ovariectomized mice. Collectively, the results demonstrate that IVA is a novel bioactive BCFA that inhibits OC differentiation, suggesting that IVA can be considered a useful material to control osteoclast-associated bone disorders, including osteoporosis.


Assuntos
Reabsorção Óssea/prevenção & controle , Diferenciação Celular , Hemiterpenos/farmacologia , Osteoclastos/citologia , Osteoporose/prevenção & controle , Ovariectomia/efeitos adversos , Ácidos Pentanoicos/farmacologia , Animais , Remodelação Óssea , Reabsorção Óssea/etiologia , Reabsorção Óssea/patologia , Feminino , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Osteoporose/patologia , Osteoporose/cirurgia , Transdução de Sinais
19.
Int J Cancer ; 149(3): 585-593, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33729548

RESUMO

The association between oophorectomy and risk of breast cancer in the general population is uncertain. The aim of our study was to determine the breast cancer rate in women from the general population after oophorectomy (performed before/after menopause), and whether this varies by use of hormone replacement therapy (HRT), hysterectomy, body mass index (BMI) and shift work. The study included 24 409 female nurses (aged ≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from cohort entry until date of breast cancer, death, emigration or end of follow-up at 31 December 2018, whichever came first. Poisson regression with log-transformed person-years as the offset examined the association between oophorectomy and breast cancer (all ages and stratified by menopausal status at time of oophorectomy). The potential modifying effect of HRT use, hysterectomy, BMI and shift work on the associations was estimated. During 502 463 person-years of follow-up, 1975 (8.1%) nurses were diagnosed with breast cancer. Bilateral oophorectomy was associated with a reduced breast cancer rate compared to nurses with preserved ovaries, adjusted rate ratio (95% confidence interval): 0.79 (0.64; 0.99). Similar associations (magnitude and direction) were detected for unilateral oophorectomy and when stratifying according to menopausal status at time of oophorectomy, but without statistical significance. Unilateral and bilateral oophorectomy is associated with a reduced breast cancer rate in women from the general population. This association is not modified by use of HRT, hysterectomy, BMI or shift work.


Assuntos
Neoplasias da Mama/epidemiologia , Terapia de Reposição Hormonal/efeitos adversos , Histerectomia/efeitos adversos , Menopausa , Ovariectomia/efeitos adversos , Adulto , Idoso , Índice de Massa Corporal , Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Dinamarca/epidemiologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco
20.
Exp Neurol ; 341: 113697, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33727095

RESUMO

Epidermal growth factor receptor (EGFR) signaling plays a substantial role in learning and memory. The upregulation of EGFR has been embroiled in the pathophysiology of Alzheimer's disease (AD). Nevertheless, most of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have been extensively studied for non-CNS diseases such as cancer and rheumatoid arthritis. TKIs targeting-based research in neurodegenerative disorders sounds to be lagging behind those of other diseases. Hence, this study aims to explore the molecular signaling pathways and the efficacy of treatment with lapatinib ditosylate (LAP), as one of EGFR-TKIs that has not yet been investigated in AD, on cognitive decline induced by ovariectomy (OVX) with chronic administration of D-galactose (D-gal) in female Wistar albino rats. OVX rats were injected with 150 mg/kg/day D-gal ip for 8 weeks to induce AD. Administration of 100 mg/kg/day LAP p.o. for 3 weeks starting after the 8th week of D-gal administration improved memory and debilitated histopathological alterations. LAP decreased the expression of GFAP, p-tau, and Aß 1-42. Besides, it reduced EGFR, HER-2, TNF-α, NOX-1, GluR-II, p38 MAPK, and p-mTOR. LAP increased nitrite, and neuronal pro-survival transduction proteins; p-PI3K, p-AKT, and p-GSK-3ß levels. Taken together, these findings suggest the role of LAP in ameliorating D-gal-induced AD in OVX rats via activating the pro-survival pathway; PI3K-Akt-GSK-3ß, while inhibiting p-mTOR, NOX-1, and p38 MAPK pathways. Moreover, this research offered a significant opportunity to advance awareness of the repositioning of TKI anti-cancer drugs for the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Galactose/toxicidade , Lapatinib/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Ovariectomia/efeitos adversos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Lapatinib/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos Wistar , Resultado do Tratamento
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